T1 RELAXATION STUDIES TOWARD ISOFORM SELECTIVE INHIBITORS OF NOS

一氧化氮合酶（NOS）将精氨酸转化为瓜氨酸， 自由基双原子一氧化氮 一氧化氮现在 作为神经系统中的重要信使分子， 内皮和免疫系统的稳态和功能。 然而，高水平的一氧化氮也被证明是 导致中毒性休克心脏病和严重的脑损伤 因此，抑制这种酶变得至关重要。 一氧化氮在各种组织中通过选择的同种型合成， 普遍存在的一氧化氮产生的性质具有严重的后果 因为不合理的副作用已经被 显示存在于非选择性抑制期间。 尽管同种型 是高度同源的，我们已经证明， 酶确实存在，酶的活性位点是 不同. 我最近建立了核磁共振参数， 观察NOS与精氨酸的顺磁弛豫效应， 几种抑制剂 铁的顺磁效应将用于 获得从Fe到每个抑制剂的质子的远距离约束 从而建立整体距离以及构象 活动场所内的限制。 我们目前的工作是针对 以获得所有三种异构体与所选抑制剂的数据。 计算机 Graphics Laboratory资源（包括MidasPlus）用于 构建各活性位点与相应抑制剂的模型 亲和力，朝向异构体选择性的合理设计 抑制剂的

Nitric oxide synthase (NOS) converts arginine to citrulline and the radical diatomic, nitric oxide. Nitric oxide is now well established as a critical messenger molecule in the neural, endothelial and immune systems for both homeostasis and function. High levels of nitric oxide, however, have been also proven to be responsible for toxic shock, cardiac disease and sever brain damage. Inhibition of this enzyme has therefore become of primary importance. Nitric oxide is synthesized in various tissues by select isoforms and ubiquitous nature of nitric oxide production has severe consequences for NOS inhibition since unreasonable side-effects have already been shown to exist during nonselective inhibition. Although the isoforms are highly homologous, we have shown that critical differences between the enzymes do exist and that the active sites of the enzymes are different. I have recently established the NMR parameters for observing the paramagnetic relaxation effects of NOS with arginine and several inhibitors. Th paramagnetic effect of the Fe will be used to obtain distant constraints from the Fe to the proton of each inhibitor and therefore establish overall distance as well as conformational restraints within the active site. Our current work is directed toward obtaining data for all three isoforms with selected inhibitors. Computer Graphics Laboratory resources, including MidasPlus, is used to construct a model of each active site together with relative inhibitor affinities, toward the rational design of isofrom selective inhibitors.